Abstract
BackgroundPancreatic cancer is one of the most lethal cancers worldwide. The aim of this study was to determine the expression pattern, clinical significance, and biological functions of Wnt5a in pancreatic cancer.MethodsImmunohistochemistry was performed to examine Wnt5a expression in 134 surgically resected pancreatic adenocarcinoma and adjacent normal pancreatic tissues. Associations of Wnt5a expression with clinicopathological factors and cancer-specific survival were analyzed. The effects of Wnt5a overexpression or silencing on the invasiveness and epithelial-to-mesenchymal transition (EMT) of pancreatic cancer cells were studied. Silencing of β-catenin by small interfering RNA was done to determine its role in the Wnt5a-mediated tumor phenotype.ResultsThe percentage of Wnt5a positive expression showed a bell-shaped pattern in pancreatic cancer tissues, peaking in well-differentiated carcinomas. The median cancer-specific survival was comparable between patients with positive versus negative expression of Wnt5a. Overexpression of Wnt5a promoted the migration and invasion of pancreatic cancer cells, whereas Wnt5a depletion had an inhibitory effect. In an orthotopic pancreatic cancer mouse model, Wnt5a overexpression resulted in increased invasiveness and metastasis, coupled with induction of EMT in tumor cells. Treatment with recombinant Wnt5a elevated the nuclear β-catenin level in pancreatic cancer cells, without altering the Ror2 expression. Targeted reduction of β-catenin antagonized exogenous Wnt5a-induced EMT and invasiveness in pancreatic cancer cells.ConclusionUpregulation of Wnt5a promotes EMT and metastasis in pancreatic cancer models, which involves activation of β-catenin-dependent canonical Wnt signaling. These findings warrant further investigation of the clinical relevance of Wnt5 upregulation in pancreatic cancer.
Highlights
Pancreatic cancer is one of the most lethal cancers worldwide
In well-differentiated carcinomas, strong immunostaining for Wnt5a was detected at the glandular luminal border, whereas in poorly differentiated carcinomas the immunoreactivity was markedly reduced
Wnt5a increases pancreatic cancer cells migration and invasiveness in vitro culture we examined the biological functions of Wnt5a in pancreatic cancer
Summary
Pancreatic cancer is one of the most lethal cancers worldwide. Pancreatic cancer is a malignant tumor of the pancreas, with an estimated 277,000 new cases and 266,000 deaths annually worldwide [1]. Pancreatic cancer has an extremely poor prognosis. The 5-year survival rate of patients with pancreatic cancer is only about 4% [2]. The lethal nature of pancreatic cancer is largely attributable to its propensity for early lymphatic invasion and distant metastasis. Accumulating evidence suggests that epithelial-to-mesenchymal transition (EMT) plays an important role in tumor progression and metastasis in various solid tumors including pancreatic cancer [5,6]. Induction of EMT in pancreatic cancer cells is associated with increased migratory capacity and invasiveness [7,8]
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